The present invention is generally related to amine oxide compounds and more particularly to amine oxide compounds and pharmaceutically acceptable salts that are antagonists of the of the Neurokinin 1 (NK-1, substance P) receptor which are prodrugs for delivery of known compounds with antagonistic activity to the Neurokinin 1 (NK-1, substance P) receptor.
A prodrug is in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. It has been shown that a molecule with optimal structural configuration and physicochemical properties for eliciting the desired therapeutic response at its target site does not necessarily possess the best molecular form and properties for its delivery to its point of ultimate action. Usually, only a minor fraction of doses administered reach the target area and since most agents interact with non-target sites as well, an inefficient delivery may result in undesirable side effects. This fact of differences in transport and in situ effect characteristics for many drug molecules is the basic reason why bioreversible chemical derivatization of drugs, i.e., prodrug formation is a means by which a substantial improvement in the overall efficacy of drugs can often be achieved. Prodrugs are designed to overcome pharmaceutically and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug.
In recent years several types of bioreversible derivatives have been exploited for utilization in designing prodrugs. Using esters as a prodrug type for drugs containing carboxyl or hydroxyl function is most popular. Further well-known are prodrug derivatives of peptides, 4-imidazolidinones and the like, described in Drugs of the Future, 1991, 16(5), 443-458 or N-oxides, described for example in U.S. Pat. No. 5,691,336.
The compounds of formula II 
are antagonists of the neurokinin receptor. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993 reviews the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyper-reactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 describes the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Further, the usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is described in Neuropeptides, 32(1), 1-49, (1998) and Eur. J. Pharmacol., 383(3), 297-303, (1999).
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The present invention relates to N-oxides of compounds of the formula 
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R1 is hydrogen or halogen; or, when n=1, R and R1, when adjacent, together can additionally bridge between the ring carbon atoms to which they are attached to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R2 and R2xe2x80x2 are hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or
R2 and R2xe2x80x2 when adjacent, and when n=1, together can additionally bridge between the ring carbon atoms to which they are attached to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 unsubstituted or substituted by one or two lower alkyl or lower alkoxy;
R3, R3xe2x80x2 are hydrogen, lower alkyl or cycloalkyl;
R4, R4xe2x80x2 are xe2x80x94(CH2)mOR6 or lower alkyl; or
R4 and R4xe2x80x2 together with the N-atom to which they are attached form a 5 or 6 member nitrogen containing heterocyclic ring of the structure 
xe2x80x83wherein said heterocyclic ring has 0 or 1 additional hetero-atoms selected the group consisting of sulfur, nitrogen and oxygen, said additional hetero-sulfur atom being a sulfide, sulfone, or sulfonyl moiety;
R5 is hydrogen, hydroxy, lower alkyl, -lower alkoxy, xe2x80x94(CH2)mOH, xe2x80x94COOR3, xe2x80x94CON(R3)2, xe2x80x94N(R3)CO-lower alkyl or xe2x80x94C(O)R3;
R6 is hydrogen, lower alkyl or phenyl;
X is xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94, xe2x80x94(CH2)mOxe2x80x94 or xe2x80x94O(CH2)mxe2x80x94;
n is 0, 1, 2, 3 or 4; and
m is 1, 2 or 3;
and to pharmaceutically acceptable acid addition salts thereof.
It has surprisingly been found that these N-oxides of the present invention have an in vitro activity on the NK1 receptor and/or may be used as prodrugs of compounds of formula 
which are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
However, the advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage. Compounds of formula II have limited water solubility, not allowing bolus injections. It was therefore useful to find derivatives of the compound of formula II to render these compounds suitable for parenteral and intramuscular application. It has been shown that N-oxides of compounds of formula I fulfill all requirements of a good prodrug.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.